This application, designed in response to RFA-DA-10-016, addresses the need for novel medications to manage cannabis dependence and addiction, recognized public health problems that are directly relevant to NIDA's mission. (-)-?9-Tetrahydrocannabinol (?9-THC), the principal active ingredient in illicitly smoked marijuana, has been shown to have positive effects in countering withdrawal symptoms that likely contribute to marijuana addiction and relapse. However, oral formulations of ?9-THC suffer from a number of clinically unfavorable properties including poor bioavailability, erratic biodisposition, and unpredictable onsets and offsets of action. Recently, we have demonstrated that inhibitors of the endocannabinoid deactivating enzyme fatty acid amide hydrolase (FAAH) that inactivates the endogenous cannabinoid receptor ligand anandamide. Unexpectedly, we have found that some of these compounds share discriminative-stimulus properties with ?9- THC, which may predict overlapping subjective effects in man. Commonality with stimulus effects of an abused drug is considered to be a desirable feature in the development of agonist-based medications for cannabis addiction. Consequently, we propose to design, synthesize, and develop novel FAAH inhibitors that may serve as viable agonist-based medications for the management of cannabis dependence and addiction. In our chemistry program, we will produce unique molecules that inhibit FAAH, produce ?9-THC-like stimulus effects and have suitable chemical and pharmacokinetic characteristics for clinical application, i.e., chemical and biochemical stability as well as selectivity over other brain esterase enzymes. In our pharmacology program, we will use in vitro measures (enzyme activity and selectivity, receptor binding, plasma and microsomal stability) and in vivo endpoints (brain penetrability, hypothermia, catalepsy, and drug discrimination) to identify novel FAAH inhibitors as 'lead'compounds. These candidates will reliably enter the brain after oral administration, have predictable and favorable time courses of action, and display ?9-THC-like stimulus properties with low side-effect liability in catalepsy and hypothermia studies. Compounds with the most advantageous preclinical characteristics will be further evaluated to gauge the time course of THC-like 'subjective-like'effects, the propensity to produce ?9-THC -like reinforcing effects, the ability to attenuate the reinforcing effects of ?9-THC, and the ability to counter withdrawal in ?9-THC-treated subjects. PUBLIC HEALTH RELEVANCE: There is a clear medical need for new candidate medications for the management of cannabis dependence and addiction. Our proposed research addresses this need with a program for the synthesis and development of novel FAAH inhibitors that increases levels of anandamide, an endogenous ligand for CB1 receptors, in the brain. Based on preliminary data showing that our novel FAAH inhibitors have some CB1 agonist-like properties, we expect to develop compounds that will be agonist-based candidate medications with excellent 'druggability', i.e., oral availability, delayed onset, and sufficiently long duration of action.